Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1

Eikermann-Haerter, Katharina; Dileköz, Ergin; Kudo, Chiho; Savitz, Sean I; Waeber, Christian; Baum, Michael J.; Ferrari, Michel D.; Maagdenberg, Arn M. J. M. van den; Moskowitz, Michael A.; Ayata, Cenk

doi:10.1172/jci36059

Cited by 189 publications

(316 citation statements)

References 97 publications

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“…28,29 Second, SD was found in the penumbra of nonmigrainous patients with middle cerebral artery infarction, increasing the infarct lesion size. 30 It is unknown whether the occurrence of SD depends on subtype or cause of stroke and whether this has influence on the long-term prognosis of stroke patients.…”

Section: Strokementioning

confidence: 99%

Concomitant Headache Influences Long-term Prognosis After Acute Cerebral Ischemia of Noncardioembolic Origin

Maino

Algra

Koudstaal

et al. 2013

Stroke

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Background and Purpose-Acute cerebral ischemia is frequently associated with headache. It is unknown whether concomitant headache reflects a partly different pathogenesis, and thus, may influence long-term prognosis after stroke. Here, we compared the long-term risk of recurrent vascular events in patients in whom a transient ischemic attack or minor ischemic stroke of noncardioembolic origin was associated with headache with those without headache. Methods-We used data from the Life Long After Cerebral ischemia (LiLAC) cohort. Participants were grouped on the basis of presence or absence of headache at presentation. We calculated the hazard ratios (HRs) and corresponding 95% confidence intervals (CI) for any first vascular event (primary outcome) or any cardiac or cerebral event (secondary outcomes). Adjustments were made for baseline clinical characteristics. Results-Of 2473 participants, 420 (17%) experienced headache during the acute event. Median follow-up was 14.1 years.For the primary outcome, the crude HR of headache versus no headache was 0.75 (95% CI, 0.66-0.89) and the adjusted HR 0.83 (95% CI, 0.71-0.97). For cardiac events the adjusted HR was 0.88 (95% CI, 0.67-1.14) and for cerebral events, 0.97 (95% CI, 0.76-1.24). The ratio of cardiac versus cerebral events, however, did not differ between the 2 groups. Participants with headache were at lower risk of vascular death (adjusted HR, 0.73; 95% CI, 0.61-0.87). Conclusions-Patients

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Section: Strokementioning

confidence: 99%

Concomitant Headache Influences Long-term Prognosis After Acute Cerebral Ischemia of Noncardioembolic Origin

Maino

Algra

Koudstaal

et al. 2013

Stroke

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“…The first and one of the most studied SD-related genes is a gain-of-function mutation in CACNA1A encoding the P/Q-type calcium channel, originally identified in familial hemiplegic migraine (FHM1) (12). Mice carrying these mutations show increased high voltage-activated calcium current, resulting in facilitated transmitter release at excitatory synapses, lower SD threshold, faster SD propagation, seizures, and early lethality (13)(14)(15). In contrast, mice with loss-of-function P/Q channel mutations show an increased SD threshold and normal lifespan (16).…”

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confidence: 99%

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected "leaky" gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations.sudden unexpected death in epilepsy | SUDEP | catecholaminergic polymorphic ventricular tachycardia | CPVT | ryanodine receptor U p to 10% of individuals with seizures of unknown cause and without known structural cardiac pathology die of sudden unexpected death in epilepsy (SUDEP), and this morbidity is second only to stroke in the number of life-years lost (1). Despite the high mortality rate, comparable to that of sudden infant death syndrome (SIDS), the exact causes are unclear, and there is no effective prediction or intervention. Cardiorespiratory dysfunction and collapse have been observed following generalized tonicclonic seizures in a small number of monitored cases (2), "near SUDEP" cases (3), and mouse SUDEP models (4-6). Genes linked with the most common cardiac LQT syndromes including LQT1 (KCNQ1), LQT2 (KCNH2/HERG), and LQT3 (SCN5A) are expressed in both the human heart and brain, where mutations in the kinetics of these membrane ion channels prolong depolarization and produce combined seizure, cardiac arrhythmia, and sudden death phenotypes (7,8). Because mutations in these ion channel genes currently explain only a small fraction of SUDEP cases (7), the search for additional genes and mechanisms is a high priority to understand and treat sudden death risk.Along with cardiac arrhythmia, recent findings in voltage-gated ion channelopathy models point to an extracardiac, central autonomic involvement of these genes in the events leading to sudden cardiac death. Spreading depolarization (SD) is a slow propagating wave of cellular depolarization that occurs in human brain and is known to contribute to transient neurological deficits during migraine ...

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“…Genetic and environmental factors modulate individual susceptibility by lowering the CSD threshold, and cortical excitation can cause sufficient elevation in extracellular K + and glutamate to initiate CSD (5,7,8,(10)(11)(12)(13)(14). Conversely, the CSD threshold also may be increased by factors that reduce the susceptibility to migraine, such as postmenopausal age and male gonadal hormones (15,16).…”

mentioning

confidence: 99%

Critical role of calcitonin gene-related peptide receptors in cortical spreading depression

Tozzi

Iure

Filippo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

117

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Cortical spreading depression (CSD) is a key pathogenetic step in migraine with aura. Dysfunctions of voltage-dependent and receptor-operated channels have been implicated in the generation of CSD and in the pathophysiology of migraine. Although a known correlation exists between migraine and release of the calcitonin gene-related peptide (CGRP), the possibility that CGRP is involved in CSD has not been examined in detail. We analyzed the pharmacological mechanisms underlying CSD and investigated the possibility that endogenous CGRP contributes to this phenomenon. CSD was analyzed in rat neocortical slices by imaging of the intrinsic optical signal. CSD was measured as the percentage of the maximal surface of a cortical slice covered by the propagation of intrinsic optical signal changes during an induction episode. Reproducible CSD episodes were induced through repetitive elevations of extracellular potassium concentration. AMPA glutamate receptor antagonism did not inhibit CSD, whereas NMDA receptor antagonism did inhibit CSD. Blockade of voltage-dependent sodium channels by TTX also reduced CSD. CSD was also decreased by the antiepileptic drug topiramate, but not by carbamazepine. Interestingly, endogenous CGRP was released in the cortical tissue in a calcium-dependent manner during CSD, and three different CGRP receptor antagonists had a dose-dependent inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. Our findings show that both glutamate NMDA receptors and voltage-dependent sodium channels play roles in CSD. They also demonstrate that CGRP antagonism reduces CSD, supporting the possible use of drugs targeting central CGRP receptors as antimigraine agents.M igraine is a common episodic headache disorder characterized by attacks that include various combinations of headache and neurologic, gastrointestinal, and autonomic symptoms. It is among the most common neurologic conditions, affecting ∼12-20% of the population. The International Headache Society classifies migraine into migraine without aura and migraine with aura, with aura defined as the complex of focal neurologic symptoms that most often precedes or accompanies an attack (1-3).Cortical spreading depression (CSD) is thought to represent a key pathogenetic step in migraine with aura (4, 5). First reported by Leão in 1944 (6), CSD is a wave of electrical activity (excitation followed by depression) that moves across the cerebral cortex after electrical or chemical stimulation. The pivotal event in the generation and propagation of CSD is a marked decrease in neuronal membrane resistance associated with massive increases in extracellular K + and neurotransmitters, as well as increases in intracellular Na + and Ca 2+ (7-9). Genetic and environmental factors modulate individual susceptibility by lowering the CSD threshold, and cortical excitation can cause sufficient elevation in extracellular K + and glutamate to initiate CSD (5,7,8,(10)(11)(12)(13)(14). Conversely, the CSD threshold also may be increased by factors that re...

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Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1

Cited by 189 publications

References 97 publications

Concomitant Headache Influences Long-term Prognosis After Acute Cerebral Ischemia of Noncardioembolic Origin

Concomitant Headache Influences Long-term Prognosis After Acute Cerebral Ischemia of Noncardioembolic Origin

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Critical role of calcitonin gene-related peptide receptors in cortical spreading depression

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